Dr. Larry S. Benardo received his Ph.D. in 1981, his M.D. in 1985, and completed a Neurology residency in 1989. He is presently an Associate Professor of Neurology and Pharmacology at SUNY-Health Science Center at Brooklyn, which with over 40 active neuroscientists, offers a rich interactive and collaborative environment. Dr. Benardo plans a lifelong career in neuroscience. With this award he can reduce his non-research duties in order to acquire new skills and focus his research career. He wants to develop expertise in using advanced optical techniques and biophysical methods. Direct visualization of interneurons will facilitate recording from these cells, and the experiments proposed. Use-dependent modifications of synaptic efficiency are central to higher cortical functions. When activity is focused and coherent, normal learning and memory formation occur; when unchecked, neuropathology results. Understanding cortical function and dysfunction must begin at the level of the local neuronal circuit. While most studies concentrate on excitation, the focus here will be on mechanisms which oppose and thus regulate excitability, namely GABAergic inhibition. The goal of the proposed experiments is to characterize inhibitory neural circuits and inhibitory neurons in the rat somatosensory cortex. Recent work postulates that inhibition in neocortex is mediated by two interneuronal populations, one for fast GABA-A, and the other for slow GABA-B inhibition. In vitro experiments will test this hypothesis with regard to the following issues: 1) Specifying the inhibitory neuron to pyramidal neuron relationship (i.e. spatial properties and unitary synaptic potentials), 2) Elucidating the physiology and morphology of inhibitory neurons, 3) Defining non-NMDA and NMDA ionotropic excitatory input onto inhibitory neurons, and 4) Defining GABAergic inhibitory input onto inhibitory neurons. Experiments will utilize standard intracellular or patch clamp recordings of layer V neurons and inhibitory interneurons in neocortical slices. Inhibitory neurons will be identified by their action on postsynaptic cells and will be marked by both extra- and intracellular labeling techniques to allow correlation of physiology and morphology. The proposed experiments will provide data on cortical information processing, and suggest mechanisms for the pathogenesis of excitotoxicity.